Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. Despite advances in cardiopulmonary resuscitation (CPR) methods, 60-80% of these arrests result in immediate death, and of the remaining, only about 5 percent are successfully resuscitated to the extent that they are returned to productive lives. Innovative approach is needed to improve the outcome of cardiac arrest and CPR. Hydrogen sulfide is a colorless gas with a characteristic rotten-egg odor found in various natural and industrial sources. Recent studies suggested that H2S is endogenously produced and exerts a host of biological effects on various targets, resulting in responses that range from cytotoxic to cytoprotective effects. It has been reported that administration of an H2S donor (Na2S) attenuates myocardial ischemia-reperfusion (IR) injury in rodents and pig. In studies presented in the Preliminary Studies section, we observed that administration of Na2S at the time of CPR markedly improved myocardial and neurological function and survival 24h after CA/CPR in mice. The robust protective effect of Na2S was associated with attenuated oxidative stress, neuronal death, and enhanced NO signal. Of note, the protective effects of Na2S were abolished by NOS3 deficiency. Importantly, administration of Na2S prevented CA/CPR-induced development of marked cerebral edema 24h after CA/CPR as demonstrated by diffusion-weighted MRI in live mice. The overall goal of this proposal is to elucidate the role of H2S and develop novel therapeutic strategies to improve outcomes of CA/CPR complicated with post-cardiac arrest syndrome. Specifically, we propose: (Aim 1) To characterize time-dependent evolution of neurological and myocardial dysfunction and systemic inflammation in a mouse model of CA/CPR with optimized post-cardiac arrest care, (Aim 2) To define the impact of hydrogen sulfide on the evolution of neurological and myocardial dysfunction after CA/CPR, (Aim 3) To define the role of NOS for the protective effects of H2S on outcome of CA/CPR, and (Aim 4) To elucidate the molecular signaling mechanisms responsible for the protective effects of hydrogen sulfide in cultured neurons, endothelial cells, and cardiomyocytes. We anticipate that proposed studies will illuminate the unique protective effects of sulfide-based approach to CA/CPR using our innovative in vivo model of murine cardiac arrest and CPR.